The USP .45 is frequently used in multiplayer because of its range, high magazine capacity and early unlock level. It has four more rounds than the M1911, as well as greater range, slightly greater recoil, and poorer hipfire accuracy. Due to its range, it is the second most powerful pistol at medium range behind the Desert Eagle. Its major flaw, however, is its mediocre hipfire accuracy compared to that of other pistols, particularly while moving.

The unsilenced USP .45 can be used by PFC Joseph Allen in the mission "S.S.D.D." and by Sgt Gary "Roach" Sanderson in "The Gulag". Its silenced variant is seen in the missions "Cliffhanger", used by Roach, and in "Contingency" (also in Roach's hands). Enemies are also seen using an unsilenced version, notably in the mission "The Only Easy Day... Was Yesterday" when they attempt to kill hostages. Like its COD4 counterpart, it comes with a non-removable, non-functional laser-aiming module under the barrel.

The USP .45 appears in two variants, much like its campaign counterpart. It can be seen with a Tactical Knife in "The Pit" and "Terminal". As with the campaign mission "The Only Easy Day...Was Yesterday", enemies in "Wetwork" will also use one when executing civilians.

The silenced version of this weapon is featured in "Evasion", "Hidden" and "Acceptable Losses", equipped with a Tactical Knife and suppressor. Enemies use it in the second level, most notably ghillie snipers if one gets too close.

The USP .45 is unlocked as soon as Create-a-Class is unlocked and largely retains its low hip-fire accuracy and recoil while maintaining longer range than the M9. It kills in three to four hits without Stopping Power, and two to three with it. As with the other pistols, the USP.45 has some of the fastest weapon draw and reloading speeds in Modern Warfare 2, but no zoom when aiming down sight and poor range.

FMJ does not work well with the USP .45 due to its low starting penetration and semi-automatic firing. However, other attachments are just as useful as they would be on other weapons. The USP .45 is also the only handgun to support a fully functional silencer, due to a glitch with the M9 silencer attachment that will still make the player show up on the map when fired, while the Magnum and Desert Eagle do not have a suppressor available. The Tactical Knife attachment speeds up melee speed, but also adds more visual recoil to the gun and slightly misaligns the iron sights. Akimbo is useful with USP.45s due to good hipfire accuracy and high close range damage, while Extended Mags allows the USP.45 to compete with the M9 for capacity.

In Hardcore with Stopping Power, the USP .45 can be a one-hit-kill sidearm at any distance. While in close to medium range, the USP .45 will still maintain a one-shot kill, even without Stopping Power.

The USP appears in Call of Duty: Modern Warfare: Mobilized as one of the two sidearms available in-game; the other being the M9. Unlike on the consoles, the USP has a 15 round magazine, as opposed to 12 rounds. It's recoil also settles much faster, resulting in more accurate shots. In singleplayer it is also incapable of a one-shot kill at close range if not headshot, but can kill in 2-3 shots at any range. Aside from this the USP is mostly the same as the console versions. However, the weapon's benefits are short-lived, since the USP is only available in one singleplayer level, "Needle in a Haystack".

In multiplayer, the USP is the default sidearm for the Coalition faction, it is the same as the M9, but due to the clearer iron sight and less usage in campaign, it is much more used than the M9. However, the iron sights are misaligned, as the real point of impact lands on top of the right dot, and its power is decreased, taking 3-4 shots to kill, depending on range. On top of this, the USP has terrible hipfire accuracy when moving, being almost as inaccurate as an LMG from the hip; but when stationary, it has much better hipfire accuracy; perfect when crouching

The USP. 45 returns in Call of Duty: Modern Warfare 3 with a changed appearance; it now has an underbarrel flashlight and a shinier, darker finish. However, the MW2 model still exists and can be found in Campaign and Spec Ops.

The USP .45 is unlocked by default to the player. It features the fastest reload of any handgun but is otherwise quite ordinary. Compared to the other low-damage handguns (The P99 and the Five Seven), the USP .45 has the lowest fire-cap and a greater amount of visual recoil (with the pistol bouncing up more than the other two). It does have an interesting range profile, the bullets dropping off from a three-hit kill slightly sooner than the other two, but maintaining their damage for longer. This makes the weapon less effective at somewhat close-range but more effective as it approaches medium-range. As with the P99, the use of a silencer will block out the iron sights, hindering long-range targeting.

The USP .45 is the sidearm equipped with the Juggernaut Recon pointstreak, along with a Riot Shield. It is also equipped with a Tactical Knife in one of the new FFA Gunplay gamemodes, All or Nothing. Infected personnel have it in all game modes except for "Striker vs Jugg"; they hold it with a Tactical Knife and with no bullets.

The USP .45 is the starting weapon for Tier 2 (Regular) Survival Mode missions. It is also available from the Weapon Armory for $250 and takes three to four shots to kill from waves 1 to 15. Downed enemies use the USP .45 as their backup weapon on the maps the player equips it as the starting weapon

The USP .45 is found in the game files and is loaded into the memory of several missions. It was most likely used for developer testing, since it uses the model of the Call of Duty: Modern Warfare 2 and the silencer model from Call of Duty 4: Modern Warfare is permanently attached.

In Call of Duty: Modern Warfare 2, on the left side of the gun there is a text that reads, "USP .45ACP" in white-gray text. It is visible in third-person.

After breaching a door, any USP .45 the player has in their inventory will gain full ammunition with a maximum of 120 rounds in reserve instead of the standard 72. However, if the player swaps this USP .45 for another weapon then picks it up again, then the ammunition will revert back to 72.

In "Museum", the USP .45 Silenced is stronger than its unsilenced variant.

In Call of Duty: Modern Warfare 2's Campaign and Spec Ops, the unsilenced USP's iron sights have the zoom of a Red Dot Sight while in ADS, whilst the silenced USP .45's iron sights have no zoom while in ADS.

If usp_scripted were to be activated in a console in some levels (particularly "The Gulag"), it will give the player a special USP that has an animation after knifing. This does not allow changing weapons.

If a player enters a private match and chooses a class with no weapons assigned to it, the player will receive a USP .45 with a Tactical Knife and no ammo.

The trademarks on the slide read "USP TACTICAL .45 AUTO". This can be seen when reloading. The suppressed version seen in "Mind the Gap" has a minor texture variation, in the form of a HK logo and "USP" on the grip, visible when reloading.

The USP .45 has a different firing sound on the Xbox 360 than the PlayStation 3.

On any Survival Mode map on the Nintendo Wii version of Call of Duty: Modern Warfare 3, if the player turns while reloading, it is possible to see a glimpse of a knife blade, as if it had a Tactical Knife.

The reload animation and the reloading sounds are off. The sound of the magazine being inserted is played before the actual magazine gets inserted into the gun. The second 'click' noise is also slightly off.